Consumption of moderate to large amounts of ethanol (Et) activates the hypothalamic-pituitary-adrenal axis (HPAA). Activation of the HPAA or hypercortisolism accompanies both short- and long-term consumption of Et and the Et withdrawal syndrome. Alcoholics often present with a pseudo-Cushing's syndrome in which some 17-40 percent of alcoholics do not respond to the dexamethasone suppression test during the first week of abstinence, suggesting an ongoing hypercortisolemic state in this group of patients. Since a relative state of elevated glucocorticoids (chronic continuous or chronic intermittent) can lead to neural changes and even cell death, particularly in the hippocampus, the progressive loss of cognitive capacity in many alcoholics may indeed be due in part to hypercortisolemia and subsequent irreversible neural damage in the hippocampus and other areas of the central nervous system. Using an intragastric cannulated rodent model and short-term (4 days) intermittent or binge-type Et administration, we have demonstrated site-specific CNS neurodegeneration in the dentate gyrus of the hippocampus, the entorhinal cortex and the piriform cortex.The observed Et-induced neurodegeneration was functionally validated as noted by the decline in learning and memory capacity in the Et-treated animals in the hippocampal-dependent Morris water maze test. Ongoing efforts to define the mechanism of Et's cytotoxicity continue by us and others. Surprisingly, the co-administration of glutamate receptor subtype antagonists or calcium uptake blocking drugs with Et are not neuroprotective, which argues against an excitotoxic basis for the neurodegeneration; however, elevated glucocorticoids exacerbate the Et-induced neurodegeneration presumably through excitotoxic mechanisms. To date the most potent cytoprotective agent in the binge-type rodent model has been shown to be furosemide, an anion transport inhibitor; however, our finding that LY-644,711, an equally potent anion transport inhibitor, is not neuroprotective would argue against a primary edema-based mechanism of neurotoxicity. Finally, with the knowledge that certain cannabinoids are neuroprotective we co-administered cannabidiol with Et and found an attenuation of neurodegeneration. Since in vitro studies have demonstrated that cannabidiol blocked glutamate-NMDA, -AMPA or -kainate receptor- mediated toxicity, it would appear that the cannabidiol site of action is downstream of receptor activation and perhaps has a generalized metabolic mechanism of neuroprotection. The ability of cannabidiol to protect against the toxicity of reactive oxygen species may underlie its cytoprotection in our binge-type Et rodent model.